药品详细

Tiotropium(噻托溴铵)

基本信息
剂型规格
适应症
药理
临床
理化性质
相互作用
文档
专利
Pathway
文献
序列

化学结构式图

中文名

噻托溴铵

英文名

Tiotropium

分子式

C₁₉H₂₂NO₄S₂

化学名

(1R,2S,4R,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3.3.1.0^{2,4}]nonan-9-ium

分子量

Average: 392.512
Monoisotopic: 392.099024577

CAS号

186691-13-4

ATC分类

R03B 未知

药物类型

small molecule

阶段

approved

商品名

同义名

基本介绍

Tiotropium is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium is a muscarinic receptor antagonist, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.

生产厂家

Boehringer ingelheim pharmaceuticals inc

封装厂家

参考

Synthesis Reference	Not Available
General Reference	Not Available

剂型

规格

化合物类型

Type	small molecule

Classes

Not Available

Substructures

Not Available

适应症

药理

Indication	Used in the management of chronic obstructive pulmonary disease (COPD).
Pharmacodynamics	Tiotropium is a long–acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3–receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies prevention of methacholine–induced bronchoconstriction effects were dose–dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site–specific effect.
Mechanism of action	Tiotropium is a muscarinic receptor antagonist, often referred to as an antimuscarinic or anticholinergic agent. Although it does not display selectivity for specific muscarinic receptors, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.
Absorption	Bioavailability is 19.5% following administration by inhalation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%.
Volume of distribution	32 L/kg
Protein binding	72% bound to plasma proteins.
Metabolism	The extent of biotransformation appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N–methylscopine and dithienylglycolic acid, neither of which bind to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450–dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. Via inhibition studies, it is evident that CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose.
Route of elimination	Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces.
Half life	5-6 days
Clearance	880 mL/min [young healthy volunteers receiving IV administration] Renal cl=326 mL/min [COPD patients (<58 years)] Renal cl=163 mL/min [COPD patients (>70 years)]
Toxicity	No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7,300, 120,000, and 850 times the recommended human daily dose on a mg/m2 basis, respectively.
Affected organisms	Humans and other mammals
Pathways	Not Available

理化性质

Properties

State

solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
water solubility	1.56e-02 g/l	ALOGPS
logP	-0.55	ALOGPS
logP	-1.8	ChemAxon
logS	-4.4	ALOGPS
pKa (strongest acidic)	10.35	ChemAxon
pKa (strongest basic)	-4.3	ChemAxon
physiological charge	1	ChemAxon
hydrogen acceptor count	3	ChemAxon
hydrogen donor count	1	ChemAxon
polar surface area	59.06	ChemAxon
rotatable bond count	5	ChemAxon
refractivity	109.18	ChemAxon
polarizability	39.69	ChemAxon

药物相互作用

Drug	Interaction
Potassium Chloride	The ulcerative effects of solid oral dosage forms of KCl may be enhanced by Tiotropium, an anticholinergic. Anticholinergics slow gastric emptying, increasing the contact time between the gastrointestinal mucosa and KCl. Prolonged exposure to KCl increases the risk of gastric and intestinal irritation and ulceration. Solid oral dosage forms of KCl should be avoided; alternatives include liquid or effervescent potassium preparations.
Pramlintide	The anticholinergic effects of Tiotropium may be enhanced by Pramlintide. Additive effects of reduced GI motility may occur. Pramlintide slows gastic emptying and should not be used with drugs that alter GI motility (e.g. anticholinergics). Consider alternative treatments or use caution during concomitant therapy.
Secretin	The stimulatory effect of Secretin may be reduced by anticholinergics such as Tiotropium. Concomitant use of Secretin and drugs with substantial anticholinergic effects should be avoided. If combination therapy must be used, Secretin efficacy should be closely monitored.
Tacrine	The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Tiotropium, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.
Trimethobenzamide	Trimethobenzamide and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Triprolidine	Triprolidine and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Trospium	Trospium and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

食物相互作用

Not Available

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